Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, yet strong genetic and environmental risk factors remain elusive. In order to effectively prevent and treat this malignancy it is critical to identify genetic polymorphisms that predispose subsets of the population to pancreatic cancer and determine how these polymorphisms modify the relationship between other risk factors and cancer. Additionally, the discovery of disease-specific genetic aberrations identified from circulating biofluids would advance the development of diagnostic tools for the early detection of pancreatic cancer. While the majority of genetic association studies have focused either exclusively on nuclear gene polymorphisms as susceptibility factors for cancer onset or on somatic alterations as indicators of cancer progression, mitochondrial DNA (mtDNA) variation has not been investigated as a risk factor for pancreatic cancer. This project will assess the association between mtDNA sequence variants and pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area (309 cases and 618 matched controls). By using the recently developed the Affymetrix Mitochondrial Resequencing Array 2.0 (MitoChip) we will be performing a comprehensive analysis of the entire mtDNA genome (~16.5kb) for associations with pancreatic cancer. The MitoChip enables the detection of both germline and acquired mutations and has been shown detect mtDNA mutations in multiple tissues (including blood). This would be the largest population-based assessment of the complete mtDNA genomic sequence and pancreatic cancer to date and has the potential to identify polymorphisms that predispose subsets of the population to this malignancy. In addition, if we determine that unique mtDNA heteroplasmic mutations are detectable in the blood of pancreatic cancer cases;these may potentially serve as powerful biomarkers for the early detection of pancreatic cancer. PUBLIC HEALTH RELEVANCE: This project will assess the association between mitochondrial DNA (mtDNA) sequence variants and pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area. By using the recently developed the Affymetrix Mitochondrial Resequencing Array 2.0 (MitoChip) we will be performing a comprehensive analysis of the entire mtDNA genome (~16.5kb) for associations with pancreatic cancer. This would be the largest population-based assessment of the complete mtDNA genomic sequence and pancreatic cancer to date and has the potential to identify polymorphisms that predispose subsets of the population to this malignancy. In addition, if we determine that unique mtDNA heteroplasmic mutations are detectable in the blood of pancreatic cancer cases;these may potentially serve as powerful biomarkers for the early detection of pancreatic cancer.